Not Applicable.
Not Applicable.
Not Applicable.
This invention relates generally to preparing vinylaromatic compounds. More specifically, it relates to preparing vinylaromatic compounds wherein the vinyl group is derived from an enolizable aldehyde or ketone and the aromatic group is derived from an arylmetal reagent. The invention also relates to preparing vinylphosphates from enolizable ketones for use in coupling reactions to prepare vinyl compounds. Vinylaromatic compounds are valuable as fine chemical intermediates and pharmaceutically active compounds. For example, nafoxidine, a vinylaromatic compound, is an estrogen receptor modulator which can be converted, via hydrogenation of the vinylic double bond, to lasofoxifene, another estrogen receptor modulator.
A classical method for the preparation of vinylaromatic compounds is the reaction of an aldehyde or ketone bearing a hydrogen on a carbon adjacent to the carbonyl group with an arylmetal reagent to form, on acidic hydrolysis, first an alcohol then a vinylaromatic compound by acid catalyzed dehydration. This is diagrammed in the top route in Scheme 1 in which the arylmetal reagent is an aryl Grignard reagent and where R, Rxe2x80x2, Rxe2x80x3 are each hydrogen or a hydrocarbyl group, Ar is an aromatic group, and X is a halide. An alternative mode of reaction that can occur between the aldehyde or ketone and the arylmetallic reagent reactants is simple xcex1-deprotonation of the aldehyde or ketone to form the enolate and the protonated aromatic group. On hydrolysis, the enolate returns the aldehyde or ketone starting material. This is diagramed in the bottom route in Scheme 1. 
The alternative mode of reaction to form the enolate can cause not only chemical yield loss, but also recovery yield loss due to problematic separations of the desired product from the alternative products. For certain combinations of aldehydes or ketones (certain R, Rxe2x80x2, Rxe2x80x3) and aryl Grignard reagents (certain Ar), the enolization reaction so dominates as to make this method practically useless for the preparation of the desired vinylaromatic compound.
Lednicer et al., J. Med. Chem. Soc., vol. 9 (1966), pp. 172-176 and Lednicer et al., J. Med. Chem. Soc., vol. 10 (1967), pp. 78-84 disclose preparations of certain 1,2-diaryl-3,4-dihydronaphthalene compounds, including nafoxidine, via reactions of corresponding 2-aryl-1-tetralone compounds with aryl Grignard reagents. Lednicer et al., in J. Med. Chem. Soc., vol. 12 (1969), pp. 881-885, later state, xe2x80x9cThe nucleus of this system [1,2-diaryl-3,4-dihydronaphthalenes] has usually been prepared by condensation of the appropriate 2-aryl-1-tetralone with the Grignard reagent of the aryl group that is to appear at the 1 position. Yields in this reaction have tended to be poor due to extensive enolization of the ketone by the Grignard reagent; large amounts of unreacted ketone are characteristically recovered.xe2x80x9d
U.S. Pat. No. 5,552,412 discloses preparations of nafoxidine (1-{4-[2-(pyrrolidin-N-yl)ethoxy]phenyl}-6-methoxy-2-phenyl-3,4-dihydronaphthalene) from 1-{4-[2-(pyrrolidin-N-yl)ethoxy]phenyl}-6-methoxy-3,4-dihydronaphthalene, a 1-aryl-3,4-dihydronaphthalene compound. (In the patent it is designated by the alternative name 1-{2-[4-(6-methoxy-3,4-dihydronaphthalen-1-yl)phenoxy]ethyl)pyrrolidine.) The 1-{4-[2-(pyrrolidin-N-yl)-ethoxy]phenyl}-6-methoxy-3,4-dihydronaphthalene was prepared by reacting an excess of a 4-[2-(pyrrolidin-N-yl)ethoxy]phenyl cerium reagent (prepared from the corresponding aryl bromide by treating sequentially with n-butyl lithium and cerium chloride) with 6-methoxy-1-tetralone, combined at xe2x88x9278xc2x0 C. and allowed to warm to room temperature, and subsequently acidifying the product mixture. In the ensuing workup, 34% of the 6-methoxy-1-tetralone was recovered prior to isolation of the desired 1-{4-[2-(pyrrolidin-N-yl)ethoxy]phenyl}-5 6-methoxy-3,4-dihydronaphthalene in 57% yield (See Step A in column 21).
Aldehydes and ketones can be converted to vinylphosphates by phosphorylation of their enolates. Bases that have typically been used to generate the enolates for phosphorylation include amines (e.g. triethylamine), amides (e.g. lithium diisopropylamide), alkoxides (e.g. potassium t-butoxide), and basic salts (e.g. potassium carbonate).
Vinyl phosphates have been used as reagents in coupling reactions to prepare vinyl compounds. Fugami et al., Chem. Lett. (1987), pp. 2203-2206 disclose reactions of certain vinylphosphates with triphenylmanganate reagent, preformed from phenyl lithium or phenyl Grignard reagent and Li2MnCl4, in the presence of a palladium catalyst provided by Pd(PPh3)4 to afford vinylbenzene compounds. Nan et al., Tetrahedron Letters, vol. 40 (1999), pp. 3321-3324 discloses reactions of cyclohexenylphosphate with arylboronic acid reagents in the presence of a palladium or nickel catalyst to afford cyclohexenyl aromatic compounds. Sahlberg et al., Tetrahedron Letters, vol. 24 (1983), pp. 5137-5138 and Sofia et al., J. Org. Chem., vol. 64 (1999), pp. 1745-1749 each disclose reactions of certain 1,3-dien-2-ol phosphates with phenyl Grignard reagent in the presence of certain phosphine ligated nickel catalysts to afford 2-phenyl-1,3-diene compounds (xcex1-vinyl-vinylbenzene compounds). Wu et al., J. Org. Chem., vol. 66 (2001), pp. 7875-7878 discloses reactions of 4-diethyl-phosphonooxycoumarins with alkyl or aryl zinc reagents in the presence of a nickel or palladium catalyst to afford 4-alkyl or 4-aryl substituted coumarins.
Takai et al., Tetrahedron Letters, vol. 21 (1980), pp. 2531-2534; Takai et al., Bull. Chem. Soc. Jpn., vol. 57 (1984), pp. 108-115; Fukarniya et al., Chem. Ind. (London), vol. 17 (1981), pp. 606-607; Sato et al., Tetrahedron Letters, vol. 22 (1981), pp. 1609-1612; Asao et al., Synthesis (1990), pp. 382-386; and Alderdice et al., Can. J. Chem., vol. 71 (1993), pp. 1955-1963 disclose, in all, reactions of certain vinylphosphates with trialkyl-, trialkenyl-, or trialkynyl-aluminum reagents in the presence of a palladium, nickel, or copper catalyst to afford vinyl-alkyl, -alkenyl, or -alkynyl compounds. Hayashi et al., Synthesis (1981), pp. 1001-1003; Armstrong et al., Can. J. Chem., vol. 60 (1982), pp. 673-675; and Danishefsky et al., J. Am. Chem. Soc., vol. 110 (1988), pp.8129-8133 disclose, in all, reactions of certain vinylphosphates with trimethylsilylmethylmagnesium halide reagents in the presence of a palladium or nickel catalyst to afford allyltrimethylsilane compounds. Okuda et al. Tetrahedron Letters, vol. 24 (1983), pp. 2015-2018 discloses reactions of certain vinyl-phosphates with phenyldimethylsilyl-aluminum and -magnesium reagents in the presence of a palladium catalyst to afford vinylsilane compounds.
Hayashi et al., Tetrahedron Letters, vol. 22 (1981), pp. 4449-4452 discloses reactions of aryl phosphates with alkyl or aryl Grignard reagents in the presence of a nickel catalyst to afford alkyl-aryl compounds and biaryl compounds, respectively.
The object of this invention is to provide an effective and efficient process for the preparation of vinylaromatic compounds. A further object of this invention is to provide such a process capable of using enolizable aldehydes and ketones to provide the vinyl group in combination with using arylmetal reagents selected from arylmagnesium reagents and aryllithium reagents to provide the aromatic group. Another object of this invention is to provide a process for preparing vinylphosphates from enolizable ketones for use in coupling reactions to prepare vinyl compounds.
A further object of this invention is to provide an advantageous process for the preparation of 1-aryl-3,4-dihydronaphthalene compounds. A specific object of this invention is to provide a advantageous processes for the preparations of 1-{4-[2-(pyrrolidin-N-yl)-ethoxy]phenyl}-6-methoxy-3,4-dihydronaphthalene and nafoxidine. Other objects and advantages of the invention will become apparent to persons skilled in the art upon reading this specification.
In general terms, the present invention provides a process for preparing a vinylaromatic compound comprising reacting an arylmetal reagent selected from arylmagnesium reagents and aryllithium reagents with a vinylphosphate in the presence of a palladium catalyst.
The present invention also provides a process for preparing a vinylphosphate comprising reacting a ketone bearing a hydrogen on a carbon adjacent to the carbonyl group (that is, an enolizable ketone) with a sterically hindered Grignard reagent and a halophosphate diester. The vinylphosphate so produced is suitable to directly use, without separation or isolation, in a coupling reaction with an arylmetal reagent. In one embodiment of the present invention, the vinylphosphate so produced is reacted with an arylmetal reagent selected from arylmagnesium reagents and aryllithium reagents in the presence of a palladium catalyst to produce a vinylaromatic compound.
In one embodiment, the present invention provides an process for the preparation of 1-aryl-3,4-dihydronaphthalene compounds comprising reacting a 3,4-dihydronaphth-1-yl phosphate compound with an arylmetal reagent selected from arylmagnesium reagents and aryllithium reagents in the presence of a palladium catalyst. In one such embodiment, the 3,4-dihydronaphth-1-yl phosphate compound is produced by reacting a 1-tetralone compound with a sterically hindered Grignard reagent and a halophosphate diester. In a more specific embodiment, the present invention provides a process for preparing I-{4-[2-(pyrrolidin-N-yl)ethoxy]phenyl}-6-methoxy-3,4-dihydronaphthalene comprising reacting a 4-[2-(pyrrolidin-N-yl)ethoxy]phenylmagnesium halide reagent with a 6-methoxy-3,4-dihydronaphth-1-yl phosphate in the presence of a palladium catalyst. In one such embodiment, the 6-methoxy-3,4-dihydronaphth-1-yl phosphate is produced by reacting 6-methoxy-1-tetralone with a sterically hindered Grignard reagent and a chorophosphate diester.
Not applicable.
Unless otherwise stated, the following terms used in the specification and claims have the meanings given below:
As used herein, the term xe2x80x9ctreatingxe2x80x9d, xe2x80x9ccontactingxe2x80x9d or xe2x80x9creactingxe2x80x9d refers to adding or mixing two or more reagents under appropriate conditions to produce the indicated and/or the desired product. It should be appreciated that the reaction which produces the indicated and/or the desired product may not necessarily result directly from the combination of two reagents which were initially added, i.e., there may be one or more intermediates which are produced in the mixture which ultimately leads to the formation of the indicated and/or the desired product. xe2x80x9cSide-reactionxe2x80x9d is a reaction that does not ultimately lead to a production of a desired product.
xe2x80x9cAlkylxe2x80x9d means a linear saturated monovalent hydrocarbon radical or a branched saturated monovalent hydrocarbon radical or a cyclic saturated monovalent hydrocarbon radical, having the number of carbon atoms indicated in the prefix. For example, (C1-C6)alkyl is meant to include methyl, ethyl, n-propyl, 2-propyl, tert-butyl, pentyl, cyclopentyl, cyclohexyl and the like. For each of the definitions herein (e.g., alkyl, alkenyl, alkoxy, aralkyloxy), when a prefix is not included to indicate the number of main chain carbon atoms in an alkyl portion, the radical or portion thereof will have twelve or fewer main chain carbon atoms. A divalent alkyl radical refers to a linear saturated divalent hydrocarbon radical or a branched saturated divalent hydrocarbon radical having the number of carbon atoms indicated in the prefix. For example, a divalent (C1-C6)alkyl is meant to include methylene, ethylene, propylene, 2-methylpropylene, pentylene, and the like.
xe2x80x9cAlkenylxe2x80x9d means a linear monovalent hydrocarbon radical or a branched monovalent hydrocarbon radical having the number of carbon atoms indicated in the prefix and containing at least one double bond. For example, (C2-C6)alkenyl is meant to include, ethenyl, propenyl, and the like.
xe2x80x9cAlkynylxe2x80x9d means a linear monovalent hydrocarbon radical or a branched monovalent hydrocarbon radical containing at least one triple bond and having the number of carbon atoms indicated in the prefix. For example, (C2-C6)alkynyl is meant to include ethynyl, propynyl, and the like.
xe2x80x9cAlkoxyxe2x80x9d, xe2x80x9caryloxyxe2x80x9d, xe2x80x9caralkyloxyxe2x80x9d, or xe2x80x9cheteroaralkyloxyxe2x80x9d means a radical xe2x80x94OR where R is an alkyl, aryl, aralkyl, or heteroaralkyl respectively, as defined herein, e.g., methoxy, phenoxy, benzyloxy, pyridin-2-ylmethyloxy, and the like.
xe2x80x9cArylxe2x80x9d means a monocyclic or bicyclic aromatic hydrocarbon radical of 6 to 10 ring atoms which is substituted independently with one to four substituents, preferably one, two, or three substituents selected from alkyl, alkenyl, alkynyl, halo, nitro, cyano, hydroxy, alkoxy, amino, mono-alkylamino, di-alkylamino and heteroalkyl. More specifically the term aryl includes, but is not limited to, phenyl, biphenyl, 1-naphthyl, and 2-naphthyl, and the derivatives thereof.
xe2x80x9cAralkylxe2x80x9d refers to a radical wherein an aryl group is attached to an alkyl group, the combination being attached to the remainder of the molecule through the alkyl portion. Examples of aralkyl groups are benzyl, phenylethyl, and the like.
xe2x80x9cHeteroalkylxe2x80x9d means an alkyl radical as defined herein with one, two or three substituents independently selected from cyano, alkoxy, amino, mono- or di-alkylamino, thioalkoxy, and the like, with the understanding that the point of attachment of the heteroalkyl radical to the remainder of the molecule is through a carbon atom of the heteroalkyl radical.
xe2x80x9cHeteroarylxe2x80x9d means a monocyclic or bicyclic radical of 5 to 12 ring atoms having at least one aromatic ring containing one, two, or three ring heteroatoms selected from N, O, or S, the remaining ring atoms being C, with the understanding that the attachment point of the heteroaryl radical will be on an aromatic ring. The heteroaryl ring is optionally substituted independently with one to four substituents, preferably one or two substituents, selected from alkyl, halo, nitro, cyano, hydroxy, alkoxy, amino, acylamino, mono-alkylamino, di-alkylamino, heteroalkyl, More specifically the term heteroaryl includes, but is not limited to, pyridyl, furanyl, thienyl, thiazolyl, isothiazolyl, triazolyl, imidazolyl, isoxazolyl, pyrrolyl, pyrazolyl, pyridazinyl, pyrimidinyl, benzofuranyl, tetrahydrobenzofuranyl, isobenzofuranyl, benzothiazolyl, benzoisothiazolyl, benzotriazolyl, indolyl, isoindolyl, benzoxazolyl, quinolyl, tetrahydroquinolinyl, isoquinolyl, benzimidazolyl, benzisoxazolyl or benzothienyl, and the derivatives thereof.
In a general sense, the present invention provides a method for the preparation of a vinylaromatic compound of the formula III from an aldehyde or ketone of the formula I via a vinylphosphate of the formula II. 
RP in formula II is hydrocarbyl, so that the vinylphosphate is a phosphate triester wherein at least one of the phosphate ester groups is a vinylphosphate ester group. Suitable hydrocarbyl groups for RP, include alkyl, aryl, and aralkyl groups. Preferred RP are methyl, ethyl, and phenyl. Alternatively, one or both of the hydrocarbyl groups RP can be another identical vinyl group.
R1 in formulas I, II, and III is hydrogen (for an aldehyde) or a hydrocarbyl group (for a ketone). R2 and R3 in formulas I, II, and III can be independently hydrogen, a hydrocarbyl group hydrocarbyl, or any substituent that does not interfere with the reaction chemistry of the invention. Suitable hydrocarbyl groups for R1, R2, and R3 include acyclic, cyclic, and heterocyclic hydrocarbyl groups, include saturated and unsaturated hydrocarbyl groups, include alkyl, heteroalkyl, aryl, heteroaryl, aralkyl, alkenyl, and alkynyl groups, as well as combinations thereof, and can be optionally substituted with one or more substituents that do not interfere with the reaction chemistry of the invention. Combinations of R1, R2, and R3 can be linked together in one or more cyclic structures.
Ar1 in formula II is an optionally substituted aryl group or heteroaryl group as defined above.
Suitable substituents for R2 and R3, for substituents on hydrocarbyl groups for R1, R2, and R3, and for substituents on aryl group or heteroaryl group Ar1 are substituents that do not interfere with the reaction chemistry. The vinylphosphate of formula II should not comprise any other substituent that is reactive to the aryl metal reagent unless it is intended to also react. One skilled in the art will recognize suitable and unsuitable substituents which can be different depending on the choice of reagents (e.g. arylmagnesium or aryllithium reagents) and other specific reaction conditions. Suitable substituents include, by example, alkoxy, aryloxy, tertiary amino, and halo. However, the aldehyde or ketone of formula I will typically be void of any other ketone or aldehyde substituent unless it is intended to also react.
The vinylphosphate can be prepared by reaction of the corresponding aldehyde or ketone with a halophosphate diester of the formula XP(xe2x95x90O)(ORP2), wherein X is a halide, preferably chloride or bromide and most preferably chloride, and RP is defined as above, in the presence of a base. Suitable bases for the preparation of vinylphosphates are known in the art and include amines (e.g. triethylamine), amides (e.g. lithium diisopropylamide), alkoxides (e.g. potassium t-butoxide), and basic salts (e.g. potassium carbonate). The vinylphosphate prepared using such bases should be preferably separated from the neutralized base coproduct (e.g. triethylammonium chloride from triethylamine, alcohol from alkoxide) prior to its reaction with the arylmetal reagent to form the vinylaromatic compound. Such neutralized bases comprise an active hydrogen and, if still present with the vinylphosphate, would quench an equivalent of arylmetal reagent to return the aryl-hydrogen compound.
The present invention provides a process for preparing the vinylphosphate by reacting a ketone with the halophosphate diester using a sterically hindered Grignard reagent for the base. The steric hindrance of the Grignard reagent substantially impedes its ability to react by addition to the ketone (the top route in Scheme 1) and thereby substantially favors its reaction to xcex1-deprotonate and enolize the ketone (the bottom route in Scheme 1). The enolate so formed then reacts with the halophosphate to form the vinylphosphate. Because the neutralized form of the sterically hindered Grignard reagent comprises a new, inert C-H bond, instead of an active hydrogen, the resulting vinylphosphate is suitable to use directly, without any separations or isolation, in a coupling reaction with an arylmetal reagent.
Suitable sterically hindered Grignard reagents have the formula R4MgX wherein R4 is a sterically hindered hydrocarbyl group and X is a halide, preferably chloride or bromide. It will be understood that the for the purpose of this invention, the xe2x80x9csterically hinderedxe2x80x9d nature of the Grignard reagent is defined functionally in relation to the specific ketone which it is to be preferentially deprotonated and enolized for phosphorylation. Thus, a ketone with lesser steric hindrance about its carbonyl group will require a Grignard reagent with greater steric hindrance in its R4 hydrocarbyl group in order for the Grignard reagent to preferentially deprotonate and enolize the ketone, and vice versa. Typically, an aldehyde is not sufficiently sterically hindered about its carbonyl group for its vinylphosphate to be prepared using a Grignard reagent for the base. For a specific ketone, this can be determined by routine phosphorylation experiments such as those illustrated in the Examples. Preferably, the sterically hindrance of the Grignard reagent is sufficient to provide at least a 75% yield, and more preferably at least a 90% yield, of the vinylphosphate from the specific ketone.
Generally, the R4 hydrocarbyl group in the sterically hindered Grignard reagent is selected from secondary alkyl groups (e.g. isopropyl), tertiary alkyl groups (e.g. tertiary butyl), and ortho-alkyl substituted aryl groups, preferably ortho,ortho-dialkyl substituted aryl groups (e.g. mesityl and 2,4,6-tri-t-butylphenyl). Mesityl Grignard reagent is generally preferred with most ketones.
The phosphorylation reaction of the ketone with the halophosphate diester using a sterically hindered Grignard reagent can be conducted without solvent or with an additional solvent that is reaction-inert. By reaction-inert solvent is meant a solvent system which does not react with the reactants or products of the reaction, or react unfavorably with the catalyst. The term solvent system is used to indicate that a single solvent or a mixture of two or more solvents can be used. Representative solvents are aromatic hydrocarbons such as benzene, toluene, xylene; aliphatic hydrocarbons such as pentane, hexane, heptane; dialkyl ethers; and cyclic ethers, and mixtures thereof. The solvent system used need not bring about complete solution of the reactants. Preferred solvents in the solvent system are ether solvents, including diethyl ether, diisopropyl ether, dibutylether, methyl-t-butylether, dimethoxyethane, diglyme, dibutyldiglyme, tetrahydrofuran, dioxane, and the like. It is generally preferred that the solvent system is anhydrous.
The ratios of the halophosphate diester, the ketone, and the sterically hindered Grignard reagent can be varied. Either reactant can be the limiting reactant and this choice can respond to other considerations, such as which is the more costly reactant to provide, which product of the unreacted excess reagent is more readily separated from the vinylaromatic product, or, if the vinylphosphate is to be used directly in a coupling reaction with an arylmetal reagent, which unreacted excess reagent is more readily tolerated in the subsequent coupling reaction. Generally the ratio of equivalents of the halophosphate diester to the ketone is in the range from 0.5:1 to 2:1. In typical embodiments, this ratio is in the range 1:1 to 1.5:1. When the vinylphosphate is to be used directly in a coupling reaction with an arylmetal reagent, without any separations or isolation, a modest excess of the halophosphate diester to the ketone is often preferred to provide substantially complete conversion of the ketone but with only a minmal amount of unreacted halophosphate diester entering the subsequent coupling reaction. Generally the ratio of equivalents of the sterically hindered Grignard reagent to the ketone is in the range from 0.5:1 to 2:1. In typical embodiments, this ratio is in the range 1:1 to 1.5:1 Typically, a modest excess of the sterically hindered Grignard reagent to the ketone is often preferred to provide substantially complete conversion of the ketone.
In typical embodiments, the phosphorylation reaction is suitably conducted at a temperature of from about 0xc2x0 C. to 100xc2x0 C., although higher temperature can be used in some embodiments.
The order of addition of the phosphorylation reaction components can be varied. All the reaction components can be mixed at a temperature below that at which reaction occurs, in any order, and then heated to the reaction temperature. Alternatively, one or more of the components can be added to a mixture of the other components that is at the desired reaction temperature. It is generally preferred to add the sterically hindered Grignard reagent last to avoid side reactions of the enolate anion in the absence of the chlorophosphate. The preferred order and manner of addition for any specific embodiment can be determined by routine experimentation with a view towards both reaction performance and chemical engineering considerations.
The vinylaromatic compound is prepared by reacting the vinylphosphate compound with an arylmetal reagent selected from arylmagnesium reagents and aryllithium reagents in the presence of a palladium catalyst. Suitable arylmagnesium reagents are selected from the group consisting of arylmagnesium salts, diarylmagnesium compounds, or mixtures thereof. Arylmagnesium salts have the general formula Ar1MgY, wherein Ar1 is an an optionally substituted aryl group or heteroaryl group as defined above and Y is an inorganic or organic salt anion. Preferred arylmagnesium salts are arylmagnesium halides, also known as aryl Grignard reagents, of the general formula Ar1MgX, wherein X is a halide anion. Especially preferred are arylmagnesium chloride and arylmagnesium bromide reagents. Diaryl magnesium compounds have the general formula Ar12Mg. Arylmagnesium halides and diarylmagnesium compounds can be prepared from arylhalides and magnesium by methods known in the art.
Suitable aryllithium reagents are aryllithium compounds of the general formula Ar1Li, wherein Ar1 is as defined above. Aryllithium compounds can be prepared by methods known in the art.
In one embodiment, the present invention provides a method for the preparation of a 1-aryl-3,4-dihydronaphthalene compound of the formula VI from a 1-tetralone compound of the formula IV via a 3,4-dihydronaphth-1-yl phosphate compound of the formula V. 
RP in formula V and Ar1 in formula VI are defined as above. In this embodiment, Ar1 is preferably a phenyl or substituted phenyl group. Preferred substituted phenyl groups include para-alkoxy substituted phenyl groups, most preferably wherein the alkoxy substituent is a 2-dialkylaminoethoxy substituent of the formula R5R6NCH2CH2xe2x80x94, wherein R5 and R6 are hydrocarbyl groups defined as for R2 and R3 above.
W in formulas IV, V and VI is a substituent on one or more of the 5, 6, 7, or 8 positions of the 1-tetralone (Formula IV) or 3,4-dihydronaphthalene (formulas V and VI) ring system, selected from substituents that do not interfere with the reaction chemistry of the invention. These are known to persons skilled in the art and can be determined by routine experimentation. Examples of suitable substituents are the same as R2 and R3 described above. The subscript n in the formulas IV, V, and VI is an integer from 0 to 4. Preferably n=1 and most preferably the substituent W is on the 6-position of the ring system. A particularly preferred substituent W is methoxy. When n=0, no substituent W is present in the formula. When n is greater than 1, the W substituents can be the same or different and are selected independently of each other.
Z in formulas IV, and V is a substituent on one or more of the 2, 3 or 4 positions of the 1-tetralone (Formula IV) or 3,4-dihydronaphthalene (formulas V and VI) ring system, and is defined as for W above. The subscript m is an integer from 0 to 3, preferably 0 or 1. When m=0, no substituent Z is present in the formula. When m=1, the substituent is preferably on the 2 position of the ring system. Particularly preferred substituents on the 2 position are aryl groups and heteroaryl groups as defined above, and most preferably phenyl. When m is greater than 1, the Z substituents can be the same or different and are selected independently of each other.
In one such embodiment, the present invention provides a process for preparing 1-{4-[2-(pyrrolidin-N-yl)ethoxy]phenyl}-6-methoxy-3,4-dihydronaphthalene (formula IX) comprising reacting a 4-[2-(pyrrolidin-N-yl)ethoxy]phenylmagnesium halide (formula VIII, wherein X is as defined above) with a 6-methoxy-3,4-dihydronaphth-1-yl phosphate compound (formula VII, wherein RP is as defined above) in the presence of a palladium catalyst. The 6-methoxy-3,4-dihydronaphth-1-yl phosphate compound can be produced from 6-methoxy-1-tetralone. 
Suitable palladium catalysts include those provided by palladium compounds and salts, in particular palladium(0) compounds and palladium(II) compounds and salts. Preferably, the palladium catalyst also comprises a ligand. Suitable ligands include monodentate, bidentate, and tridentate ligands comprising nitrogen or phosphorus as ligating atom. Preferred ligands include triorganophosphines, triorganophosphites, and aromatic nitrogen heterocycle ligands. Examples of preferred ligands include triarylphosphines (e.g. triphenylphosphine), bidentate bis(diarylphosphino) compounds (e.g. 1,1xe2x80x2 -bis(diphenylphosphino)ferrocene), trialkylphosphites (e.g. triisopropylphosphite), and pyridine-type ligands (e.g. pyridine, bipyridine). Particular ligands include those illustrated in the working Examples herein.
Suitable and optimal ratios of the ligand to catalyst metal depend on a number of other parameters, including the identity of the ligand, the concentration of the catalyst, the reaction temperature, the reactivity of the reactants, the solvent, and the like, and can be readily determined by routine experimentation. Typically the ratio of the ligand to the catalyst metal is in the range of 1:1 to 4:1. However, the amount of ligand in the reaction mixture can be in excess of the maximum ratio that could be bound to the catalyst metal.
The active catalyst can be prepared in advance of its introduction to the reaction mixture, or can be generated in the reaction mixture. It is believed that the active catalyst in the reaction is a palladium(0) catalyst. The active catalyst can be provided by a preformed ligated palladium(0) compound (e.g. tetrakis(triphenylphosphine)palladium(0)) or can be provided by combining in solution, either ex situ or in situ to the reaction mixture, a suitable ligand with a suitable palladium(0) source (e.g. tris(dibenzylideneacetone)palladium(0)). When the catalyst is provided by a palladium(II) compound or salt, the active catalyst is believed to be generated by reduction of the palladium(II) compound or salt either ex situ or in situ to the reaction mixture. Generally, the arylmetal reagent is capable of reducing the palladium(II) to generate the active catalyst in situ. This can be determined by routine experimentation. Suitable reductants for ex situ generation of the active catalyst from palladium(II) sources are known in the art and include organomagnesium halide reagents (e.g. methylmagnesium halide) and various hydride reagents (e.g. sodium bis(2-methoxyethoxy)-aluminum dihydride). Preferably the palladium(II) is combined with ligand prior to its reduction. The palladium(II) can be provided as a preformed ligated palladium(II) compound (e.g. dichlorobis(triphenylphosphine)palladium(II)) or can be provided by combining in solution a suitable ligand with a suitable palladium(II) compound (e.g. dichlorobis(acetonitrile)palladium(II)) or salt. Suitable palladium(II) salts include the salts having the general formula PdYxe2x80x22, wherein Yxe2x80x2 is an inorganic or organic salt anion. Preferred palladium(II) salts include the chlorides, bromides, carboxylates (e.g. formate, acetate, stearate) and acetylacetonates. Generally, anhydrous palladium salts are preferred.
The coupling reaction of the arylmetal reagent with the vinylphosphate can be conducted without solvent or with an additional solvent that is reaction-inert. By reaction-inert solvent is meant a solvent system which does not react with the reactants or products of the reaction, or react unfavorably with the catalyst. The term solvent system is used to indicate that a single solvent or a mixture of two or more solvents can be used. Representative solvents are aromatic hydrocarbons such as benzene, toluene, xylene; aliphatic hydrocarbons such as pentane, hexane, heptane; dialkyl ethers; and cyclic ethers, and mixtures thereof. The solvent system used need not bring about complete solution of the reactants. Preferred solvents in the solvent system are ether solvents, including diethyl ether, diisopropyl ether, dibutylether, methyl-t-butylether, dimethoxyethane, diglyme, dibutyldiglyme, tetrahydrofuran, dioxane, and the like. It is generally preferred that the solvent system is anhydrous.
The ratio of the arylmetal reagent to the vinylphosphate can be varied. Either reactant can be the limiting reactant and this choice can respond to other considerations, such as which is the more costly reactant to provide and which product of the unreacted excess reagent is more readily separated from the vinylaromatic product. Generally the ratio of equivalents of arylmetal reagent to moles of vinylphosphate ranges from 0.5:1 to 2:1. (One mole of diarylmagnesium reagent is counted as two equivalents of arylmagnesium reagent.)
In typical embodiments, this ratio is in the range 1:1 to 1.5:1. A modest excess of arylmetal reagent over vinylphosphate is often preferred to compensate for side reactions that nonselectively deplete the arylmetal reagent; for example, biaryl coupling.
In the coupling reaction of the arylmetal reagent with the vinylphosphate, the palladium catalyst is present in catalytic amounts, meaning less than stoichiometric relative to the reactants. The mole ratio of the catalyst to the vinylphosphate to be reacted can be varied, but should be a catalytic ratio of about 1:10 or less. The minimum amount of catalyst relative to the vinylphosphate depends on the activity of the specific catalyst composition, the specific vinylphosphate and arylmetal reagent to be reacted, the reaction temperature, the concentration of the reactants and catalyst in the solution, and the maximum time allowed for completion of the reaction, and can be readily determined by routine experimentation. In typical embodiments, a suitable mole ratio of the palladium catalyst to vinylphosphate is in the range of 1:10,000 to 1:10.
In typical embodiments, the coupling reaction is suitably conducted at a temperature of from about 20xc2x0 C. to 100xc2x0 C., although higher temperature can be used in some embodiments.
The order of addition of the coupling reaction components can be varied. All the reaction components can be mixed at a temperature below that at which reaction occurs, in any order, and then heated to the reaction temperature. Alternatively, one or more of the components can be added to a mixture of the other components that is at the desired reaction temperature. For larger scale operation of the process, it is generally preferred to gradually add either the arylmetal reagent or the vinylphosphate to a mixture of the other components at the desired reaction temperature in order to control the exothermic heat release of the reaction by the rate of the addition. The preferred order and manner of addition for any specific embodiment can be determined by routine experimentation with a view towards both reaction performance and chemical engineering considerations.
The vinylaromatic compound can be separated from the reaction mixture and recovered by known methods.